Prostate cancer is the most common cancer in western males, and is the third leading cause of cancer mortality due to a high incidence rate. Based on global estimates, prostate cancer accounted for more than 900,000 of total cases (only a little lower than lung cancer and bronchiolar carcinoma (1,095,200)) and nearly 260,000 deaths (approximately 6% of the total cancer deaths) in men in 2008. In curable early stages, prostate cancer in situ can be diagnosed by prostate-specific antigen (PSA) test and cured via surgical excision or radiotherapy. Most prostate cancer patients respond to androgen deprivation therapy (ADT) in a certain period. The mechanism of ADT is to block or decrease the activity of androgen receptors (AR) by reducing the androgen level, thereby inhibiting the activation of the androgen-dependent signaling pathway. However, almost all patients have progressed to “castration-resistant prostate cancer” (CRPC).
Functional androgen receptor (AR) signaling is necessary for the development of prostate cancer. AR signaling is absent or weak in androgen insensitivity syndrome and spinal and bulbar muscular atrophy patients, which results in underdeveloped prostates that do not produce carcinomas. It has become clear that AR expression and signaling remains intact as the disease evolves from androgen-sensitive cancer to hormone refractory prostate cancer (HRPC). Genetic and epigenetic changes mean that prostate tumors continue to rely on AR growth signaling, and they thus remain targets of ‘hormonal’ therapy. The development of new strategies and new drugs that more effectively abrogate AR signaling will probably result in important clinical benefits.
The AR, the gene for which is located on chromosome Xq11-12, is a member of the steroid hormone receptor family of ligand-activated nuclear transcription factors. The AR contains four functional regions: an amino terminal regulatory domain (AF-1 site), a DNA-binding domain composed of two zinc fingers, a hinge region containing a nuclear localization signal, and a carboxy-terminal ligand-binding domain (AF-2 site). Unligated ARs are located primarily in the cytoplasm, and are bound to heat shock proteins (HSPs) 90, 70, 56, and 23, which stabilize the ARs' tertiary structure in a conformation that permits androgen binding. Androgen binds to the AR, results in dissociation of HSPs from the AR, causing dimerization of the AR and subsequent tyrosine kinase phosphorylation, resulting in translocation of the AR to the nucleus. Once inside the nucleus, the AR binds to androgen response elements located in the promoter and enhancer regions of target genes, resulting in concomitant recruitment of co-regulatory proteins and formation of an active transcription complex. Co-regulatory proteins form a bridge between the AR, the preinitiation complex, and RNA poly-merase; coactivators facilitate transcription by recruiting protein complexes to DNA that alter the chromatin structure to a more transcriptionally active form, and co-repressors mediate chromatin condensation and silence transcription.
AR gene amplification has been reported in 25%-30% of patients with HRPC but is present at very low rates (1-2%) in those with primary prostate cancer, indicating that AR gene amplification is related to the development of HRPC. AR gene amplification highlights the strong selective pressure for continued AR signaling as tumors evolve in androgen-deprived environments, and provides the impetus for the development of more effective inhibition of AR signaling. Point mutations in AR can result in altered ligand specificity such that mutated ARs can be activated by non-androgenic ligands such as anti-androgens.
Bicalutamide (trade name: Casodex) is the most commonly used anti-androgen drug, which inhibits AR in hormone-sensitive prostate cancer. However, Bicalutamide cannot effectively inhibit AR activity when the cancer becomes hormone-resistant. Novel AR antagonist MDV-3100, developed by Medivation Inc., can effectively suppress the combination of androgen and AR protein, and block translocation of AR to the nucleus and recruitment of coactivators of the ligand-receptor complex. So far, none have found that MDV-3100 would become an agonist and promote cancer development in AR-overexpressed tumors. In May 21, 2012, MDV-3100 entered into the pre-registration stage.
Up to now, a series of AR antagonists have been disclosed by some patent applications, including PCT Patent Application Publications WO 2010/092371, WO 2011/008543, WO 2012/011840, and WO 2012/015723, etc.
Although a series of AR antagonists for treating prostate cancer has been disclosed, there remains a need to develop new compounds with better efficacy. After continuous efforts, the present invention provides compounds of formula (I), and shows that the compounds having such structure exhibit excellent effects and actions.